|Budget Amount *help
¥2,400,000 (Direct Cost : ¥2,400,000)
Fiscal Year 1997 : ¥800,000 (Direct Cost : ¥800,000)
Fiscal Year 1996 : ¥900,000 (Direct Cost : ¥900,000)
Fiscal Year 1995 : ¥700,000 (Direct Cost : ¥700,000)
The transcriptional activator IRF-1 was originally identified as a regulator of the interferon system. We have previously demonstrated that that IRF-1 acts as a tumor suppressor and a regulator of cell cycle and apoptosis. To investigate further the role of IRF-1 in the regulation of cell cycle and apoptosis, we analyzed the cellualar responses to DNA damage in cells from mice lacking IRF-1.
We observed that DNA damage-induced apoptosis in mitogen-activated mature Tlymphocytes but not in thymocytes is dependent IRF-1, and that mitogen induction of the Caspace-1 gene IRF-1-dependent. On the other hand, the tumor suppressor p53 regulates apoptosis in thymocytes, but not in mitogen-activated mature Tlymphocytes. Thus two different anti-oncogenic transcription factors, IRF-1 and p53, are required for distinct apoptotic pathways in Tlymphocytes.
In the case of fibroblasts DNA-damage induces cell cycle arrest but not apoptosis. We observed that IRF-1 lacking EFs are deficient in their ability
to undergo DNA damage-induced cell cycle arrest ; a phenotype similar to that observed in EFs lacking p53. Furthermore, we showed that transcriptional induction of the gene encoding the cell cycle inhibitor p21 by DNA-damage is dependent on both factors, and that the p21 promoter is activated by both. These studies revealed that p53 and IRF-1 possess both non-overlapping and overlapping functions in different type of cells, and also demonstrates a unique example of two tumor suppressor transcription factors which functionally converge to regulate the cell cyclethrough activation of a common target (s).
In addition, we purified an IRF-1 association molecule which was revealed to be identical to nucleophosmin (NPM), and found that NPM inhibited the transcriptional activity of IRF-1. Moreover, overexpression of NPM in cells resulted in malignant transformation. These results suggest the possible involvement of NPM in inactivation IRF-1-dependent anti-oncogenic surveillance in human cancer development. Less